Disordered ganglioside localization in the Alzheimer’s disease brain

Abstract

AbstractBackgroundAlzheimer’s disease (AD) is a progressive dementia that impairs memory and cognition. Gangliosides are glycosphingolipids enriched within the central nervous system and known to alter the secondary structure of amyloid beta deposits, a hallmark of AD (Choo‐Smith et al., 1997). The ganglioside GM1 is known to exert neuroprotective properties and was proposed as a therapeutic for AD (Svennerholm, 1994). In support of this, intraventricular administration of GM1 decreased amyloid beta deposits and provided clinical benefit (Augustinsson et al., 1997). Pre‐clinical work has since demonstrated a shift from complex GM1 species to simple GM2 and GM3 is linked to neurodegenerative pathogenesis (Wang & Whitehead, 2020). However, the ganglioside GM1 also converts amyloid beta to a toxic form with beta sheet structure (Yamamoto et al., 2007), and acts as a seed for amyloid beta fibrillogenesis (Yanagisawa et al., 1995). It is possible that different GM1 subtypes may be responsible for varying affects. Understanding the profile of GM1 subtypes in the AD brain may be a key step in capitalizing on its therapeutic potential. We investigate the ratio between 18 and 20 carbon subtypes of GM1 and simple ganglioside species in post‐mortem human AD brain tissue and non‐AD controls. Brain regions interrogated include the entorhinal cortex, basal forebrain, anterior commissure and hippocampus.MethodNeuroanatomical regions of interest (ROIs) were blocked from neuropathologically confirmed AD and non‐AD brains and stored in 10% formalin. Samples were prepared for matrix assisted laser desorption ionization imagining mass spectrometry (MALDI‐IMS) (Caughlin et al., 2017). MALDI‐IMS was performed in reflectron negative mode. Matching ROIs in AD and non‐AD samples (n = 5) were selected using TissueView software. Mass spectra were normalized by area under curve and peaks corresponding to gangliosides were statistically analyzed.ResultNon‐AD brains demonstrated distinct d20:1/d18:1 ratios of both simple and complex gangliosides between different brain regions. This expression profile was lost in the AD brain samples. Additionally, a significant decrease in this ratio was observed in AD compared to non‐AD samples in several brain regions.ConclusionGanglioside dysregulation and a decrease in the d20:1/d18:1 ratios in multiple brain regions are critical pathological biomarkers of AD.